Alternative titles; symbols
HGNC Approved Gene Symbol: PDE3A
SNOMEDCT: 720568003;
Cytogenetic location: 12p12.2 Genomic coordinates (GRCh38): 12:20,368,537-20,688,583 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p12.2 | Hypertension and brachydactyly syndrome | 112410 | Autosomal dominant | 3 |
Cyclic nucleotide phosphodiesterases (PDEs) comprise a complex group of enzymes, and at least 5 major PDE families or classes with distinctive properties have been identified. Members of the cGMP-inhibited cAMP PDE (cGI-PDE) family, such as PDE3A, are characterized by high affinity for cAMP and cGMP and competitive inhibition of their cAMP hydrolytic activity by cGMP and certain positive inotropic agents (Meacci et al., 1992).
Meacci et al. (1992) cloned a cDNA for a myocardial cGI-PDE, PDE3A, from a human heart cDNA library. The ORF encodes a predicted protein of 125 kD. A single mRNA species hybridized with a 4-kb EcoRI restriction fragment of the cDNA containing the entire ORF. The C-terminal region of the deduced amino acid sequence contains a putative catalytic domain conserved among mammalian PDE families.
Tang et al. (1997) used RT-PCR to identify the PDE3 enzyme expressed in human platelets. They found that the enzyme is encoded by the same gene as myocardial PDE3A, although they did not exclude the possibility of alternative splicing at the N terminus.
By immunocytochemical analysis of human sperm, Lefievre et al. (2002) detected PDE3A in the postacrosomal segment of the sperm head. Western blot analysis detected PDE3A at an apparent molecular mass of 97 kD, and most PDE3A protein was in the soluble fraction.
By RNA in situ hybridization, Maass et al. (2015) demonstrated chondrogenic Pde3a expression in developing mice at embryonic days 12.5 and 13.5 in domains involved in digit formation.
Meacci et al. (1992) obtained direct proof that the cAMP hydrolytic activity of PDE3A was inhibited by cGMP.
By analyzing deletion mutants, Tang et al. (1997) found that deletion of the N terminus of PDE3A enhanced its hydrolysis of cGMP relative to cAMP. Thus, the authors suggested, the role of the divergent N termini of various PDEs could be to exert substrate specificity.
In 6 unrelated families with hypertension and brachydactyly syndrome (HTNB; 112410), Maass et al. (2015) identified heterozygous missense mutations clustered in exon 4 of the PDE3A gene (123805.0001-123805.0006). Functional analysis demonstrated that the mutations increase protein kinase A-mediated PDE3A phosphorylation, resulting in a gain of function with increased cAMP-hydrolytic activity and enhanced cell proliferation. In addition, levels of phosphorylated VASP (601703) were reduced, and levels of PTHRP (PTHLH; 168470) were dysregulated. Maass et al. (2015) suggested that these mutations cause hypertension by contributing to a general increase in peripheral vascular resistance.
Mammalian oocytes are physiologically arrested in prophase I, i.e., prophase of the first meiotic division, until shortly before ovulation. Meiotic maturation of mammalian and amphibian oocytes in vitro is blocked by cAMP. PDE3A is primarily responsible for hydrolysis of oocyte cAMP. Masciarelli et al. (2004) studied Pde3a-deficient mice generated by homologous recombination. The Pde3a -/- females were viable and ovulated a normal number of oocytes but were completely infertile, because ovulated oocytes were arrested at the germinal vesicle stage and therefore could not be fertilized. Pde3a -/- oocytes lacked cAMP-specific PDE activity, contained increased cAMP levels, and failed to undergo spontaneous maturation in vitro (up to 48 hours). Meiotic maturation in the deficient oocytes were restored by inhibiting protein kinase A (PKA; see 176911) with a chemical agent or by injection of protein kinase inhibitor (PKI; see 606059) peptide or mRNA encoding phosphatase CDC25 (157680), which confirmed that increased cAMP-PKA signaling is responsible for the meiotic blockade. Pde3a -/- oocytes that underwent germinal vesicle breakdowns showed activation of maturation promoting factor (MPF) and MAPK (see 176872), completed the first meiotic division extruding a polar body, and became competent for fertilization by spermatozoa. The work of Masciarelli et al. (2004) provided genetic evidence indicating that resumption of meiosis in vivo and in vitro requires PDE3A activity. Inhibition of oocyte maturation as a potential strategy for contraception was suggested.
In 30 affected members of a large 7-generation Turkish family with hypertension and brachydactyly syndrome (HTNB; 112410), originally reported by Bilginturan et al. (1973), Maass et al. (2015) identified heterozygosity for a c.1334C-A transversion (c.1334C-A, NM_000921) in exon 4 of the PDE3A gene, resulting in a thr445-to-asn (T445N) substitution at a residue within a highly conserved domain. The mutation was not found in 52 unaffected family members, in 200 unrelated Caucasian controls, or in the 1000 Genomes Project or Exome Variant Server databases. Expression of the BDE-associated gene PTHLH (168470) was significantly downregulated in chondrogenically induced patient fibroblasts compared to age- and sex-matched controls. Functional analysis in HeLa cells showed significantly reduced cAMP levels with the T445N mutant compared to wildtype, indicating a gain-of-function mutation. In HeLa cell proliferation assays as well as in patient-derived vascular smooth muscle cells, Maass et al. (2015) found higher mitotic rates with the T445N mutant than wildtype PDE3A, consistent with the hyperplastic arterial walls observed in affected individuals.
In 3 affected members over 2 generations of a French family with hypertension and brachydactyly syndrome (HTNB; 112410), Maass et al. (2015) identified heterozygosity for a c.1333A-G transition (c.1333A-G, NM_000921) in exon 4 of the PDE3A gene, resulting in a thr445-to-ala (T445A) substitution at a residue within a highly conserved domain. The mutation was not present in 3 unaffected family members. Functional analysis in HeLa cells showed significantly reduced cAMP levels with the T445A mutant compared to wildtype, indicating a gain-of-function mutation.
In 4 affected members over 3 generations of a family from the United States with hypertension and brachydactyly syndrome (HTNB; 112410), Maass et al. (2015) identified heterozygosity for a c.1334C-G transversion (c.1334C-G, NM_000921) in exon 4 of the PDE3A gene, resulting in a thr445-to-ser (T445S) substitution at a residue within a highly conserved domain. The mutation was not present in 3 unaffected family members. Functional analysis in HeLa cells showed significantly reduced cAMP levels with the T445S mutant compared to wildtype, indicating a gain-of-function mutation.
In an affected individual from a South African family with hypertension and brachydactyly syndrome (HTNB; 112410), Maass et al. (2015) identified heterozygosity for a c.1339G-A transition (c.1339G-A, NM_000921) in exon 4 of the PDE3A gene, resulting in an ala447-to-thr (A447T) substitution at a residue within a highly conserved domain. The mutation was not present in 4 unaffected family members. Functional analysis in HeLa cells showed significantly reduced cAMP levels with the A447T mutant compared to wildtype, indicating a gain-of-function mutation.
In 4 affected individuals from a 3-generation Canadian family with hypertension and brachydactyly syndrome (HTNB; 112410), Maass et al. (2015) identified heterozygosity for a c.1340C-T transition (c.1340C-T, NM_000921) in exon 4 of the PDE3A gene, resulting in an ala447-to-val (A447V) substitution at a residue within a highly conserved domain. The mutation was not found in an unaffected family member. Functional analysis in HeLa cells showed significantly reduced cAMP levels with the A447V mutant compared to wildtype, indicating a gain-of-function mutation.
In 6 affected individuals from a 3-generation Canadian family with hypertension and brachydactyly syndrome (HTNB; 112410), Maass et al. (2015) identified heterozygosity for a c.1346G-T transversion (c.1346G-T, NM_000921) in exon 4 of the PDE3A gene, resulting in a gly449-to-val (G449V) substitution at a residue within a highly conserved domain. The mutation was not detected in 5 unaffected family members. Functional analysis in HeLa cells showed significantly reduced cAMP levels with the G449V mutant compared to wildtype, indicating a gain-of-function mutation.
Bilginturan, N., Zileli, S., Karacadag, S., Pirnar, T. Hereditary brachydactyly associated with hypertension. J. Med. Genet. 10: 253-259, 1973. [PubMed: 4774535] [Full Text: https://doi.org/10.1136/jmg.10.3.253]
Lefievre, L., de Lamirande, E., Gagnon, C. Presence of cyclic nucleotide phosphodiesterases PDE1A, existing as a stable complex with calmodulin, and PDE3A in human spermatozoa. Biol. Reprod. 67: 423-430, 2002. [PubMed: 12135876] [Full Text: https://doi.org/10.1095/biolreprod67.2.423]
Maass, P. G., Aydin, A., Luft, F. C., Schachterle, C., Weise, A., Stricker, S., Lindschau, C., Vaegler, M., Qadri, F., Toka, H. R., Schulz, H., Krawitz, P. M., and 35 others. PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nature Genet. 47: 647-653, 2015. [PubMed: 25961942] [Full Text: https://doi.org/10.1038/ng.3302]
Masciarelli, S., Horner, K., Liu, C., Park, S. H., Hinckley, M., Hockman, S., Nedachi, T., Jin, C., Conti, M., Manganiello, V. Cyclic nucleotide phosphodiesterase 3A-deficient mice as a model of female infertility. J. Clin. Invest. 114: 196-205, 2004. [PubMed: 15254586] [Full Text: https://doi.org/10.1172/JCI21804]
Meacci, E., Taira, M., Moos, M., Jr., Smith, C. J., Movsesian, M. A., Degerman, E., Belfrage, P., Manganiello, V. Molecular cloning and expression of human myocardial cGMP-inhibited cAMP phosphodiesterase. Proc. Nat. Acad. Sci. 89: 3721-3725, 1992. [PubMed: 1315035] [Full Text: https://doi.org/10.1073/pnas.89.9.3721]
Tang, K. M., Jang, E. K., Haslam, R. J. Expression and mutagenesis of the catalytic domain of cGMP-inhibited phosphodiesterase (PDE3) cloned from human platelets. Biochem. J. 323: 217-224, 1997. [PubMed: 9173884] [Full Text: https://doi.org/10.1042/bj3230217]